Huntington's disease (HD) is a dominantly inherited, incurable neurodegenerative disease affecting primarily the striatum and corticostriatal pathway. Although the ultimate fate of HD is selective neurodegeneration in striatum and cortex, emerging evidence suggests that dysregulated information processing in the corticostriatal circuit, rather than death alone, underlies HD neuropathophysiology. In striatum, for example, dysregulated corticostriatal-dependent glutamatergic signaling and alterations in the neurochemical milieu result in a host of abnormal striatal firing patterns long before cell loss. Consistent with this view is the fact that GLT1, which is the primary glutamate (GLU) transporter responsible for regulating synaptic levels of GLU, is dysfunctional in striatum of HD mouse models. As a result, the level of striatal ascorbate (vitamin C;AA), which is an antioxidant vitamin directly linked to the degree of GLU uptake and corticostriatal excitability, is markedly decreased in these models. Uptake of GLU and AA release, moreover, modulate excitability of striatum by shaping the firing patterns of striatal neurons. Because proper levels of both GLU uptake and AA in striatum are necessary for behavioral output, these mechanisms likely play key roles in HD neuropathology. Interestingly, the ?-lactam antibiotic ceftriaxone upregulates the functional expression of GLT1 and attenuates multiple signs of the HD behavioral phenotype in the R6/2 mouse, which is the most characterized HD model. Therefore, the overall goal of the proposed research is to characterize the effects of a ceftriaxone-mediated increase in GLU uptake via GLT1 on the neurophysiology of HD. We hypothesize that ceftriaxone will normalize the altered activity patterns of striatal neurons and reverse deficient striatal AA in the R6/2 mouse. We will test our hypothesis with two parallel approaches. In one we will use electrophysiology to record activity of striatal neurons in freely behaving R6/2 mice and wild-type littermate controls treated with either ceftriaxone or vehicle. We will record spike activity of single-units and local field potentials of neuronal ensembles to investigate the role of GLU uptake on behaviorally relevant striatal activity. In separate, but similarly treated animals, we will use voltammetry coupled with cortical stimulation to monitor the effects of glutamate uptake on corticostriatal-dependent release of AA in striatum of R6/2 mice. These studies will provide the basis for evaluating ceftriaxone as a potential therapy for HD. Unfortunately, there are currently no effective cures or treatments for HD. Because HD affects ~30,000 people in the United States and ~150,000 more are at risk for inheriting the gene, further research on HD has significant public health implications.